Short-Term Changes in Arterial Inflammation Predict Long-Term Changes in Atherosclerosis

Short-Term Changes in Arterial Inflammation Predict Long-Term Changes in Atherosclerosis Progression: Supplementary Material

1 Correlations between changes in MDS TBR Measured by PET and Vessel Wall Anatomy Measured by MRI:

In sensitivity analyses, we additionally examined the strengths of associations between the percent change in MDS TBR at 6 months and changes in MWA and MWT at 24 months as continuous variables. The percent change in MDS TBR was moderately correlated to percent change in MWA (Pearson R = 0.29), which trended towards statistical significant (p=0.06). Similar results were obtained for the relationship between percent change in MDS TBR and percent change in MWT (Pearson R = 0.27, p = 0.08).

2 Supplementary Tables:

Supplementary Table 1: Associations between Additional Baseline Characteristics and Change in Mean Wall Thickness at 24 Months on Univariate Analysis

Variable / Beta estimate (SE) / p-value
Clinical Characteristics
Age / 0.039 (0.468) / 0.93
Current smoker / -6.422 (11.827) / 0.59
Male / 8.358 (8.406) / 0.33
Baseline coronary heart disease / 7.488 (10.274) / 0.47
Baseline history of diabetes / -7.441 (8.070) / 0.36
Baseline history of hypertension / -8.758 (8.396) / 0.30
Body mass index / 1.563 (0.865) / 0.07
Systolic blood pressure / -0.264 (0.268) / 0.33
Baseline Anatomic Characteristics on MRI
Baseline mean wall area on MRI / -2.067 (0.478) / <0.001
Baseline mean wall thickness of MRI / -76.944 (13.948) / <0.001
Biochemical Characteristics
Baseline HDL / 0.308 (0.277) / 0.27
Baseline LDL / 0.022 (0.194) / 0.91
Baseline eGFR / 0.371 (0.329) / 0.27
Baseline HbA1C / -0.584 (5.174) / 0.91
Baseline IL6 concentration / -0.971 (0.867) / 0.27
Baseline CRP concentration / -0.947 (1.422) / 0.51
Baseline PAI1 activity / 0.900 (0.407) / 0.03

CRP = C-reactive protein, eGFR = estimated glomerular filtration rate, HbA1C = hemoglobin A1C, HDL = high density lipoprotein, IL-6 = interleukin-6, LDL = low density lipoprotein, MRI = magnetic resonance imaging, PAI-1 = Plasminogen activator inhibitor-1

Supplementary Table 2: Association between absolute changes in MWA and MWT at 24 months in participants with or without evidence of increased arterial inflammation

Estimate (SE) / p-value / Adjusted R2 of Model
Association between increased arterial inflammation at 6 months and absolute change in MWT on MRI at 24 months
Univariate Model / 0.14 (0.07) / 0.059 / 0.06
Multivariable Model 1* / 0.18 (0.08) / 0.026 / 0.07
Multivariable Model 2** / 0.13 (0.06) / 0.033 / 0.41
Association between increased arterial inflammation at 6 months and absolute change in MWA on MRI at 24 months
Univariate Model / 4.01 (2.14) / 0.068 / 0.06
Multivariable Model 1* / 4.42 (2.41) / 0.074 / 0.02
Multivariable Model 2*** / 4.51 (1.70) / 0.012 / 0.41

*Covariates: Age, gender, treatment allocation. **Covariates: PAI1 activity, baseline MWT on MRI. ***Covariates: PAI1A0, baseline MWA on MRI. Note: MWT and MWA were strongly correlated, therefore baseline MWT was used as a covariate in the analysis examining changes in MWT and baseline MWA was used in the analysis examining changes in MWA. BMI = body mass index, FDG = FDG= 18-fluorodeoxyglucose, MRI = Magnetic Resonance Imaging, MWT = mean wall thickness, MWA = mean wall area, PAI1 = Plasminogen activator inhibitor-1, PET = positron emission tomography.

Supplementary Table 3: Association between percent changes in MWA and MWT at 6 months in participants with or without evidence of increased arterial inflammation

Estimate (SE) / p-value / Adjusted R2 of Model
Association between increased arterial inflammation at 6 months and percent change in MWT on MRI at 6 months
Univariate Model / 7.93 (3.98) / 0.053 / 0.08
Multivariable Model 1* / 10.52 (4.16) / 0.017 / 0.11
Multivariable Model 2** / 8.24 (3.54) / 0.027 / 0.27
Association between increased arterial inflammation at 6 months and percent change in MWA on MRI at 6 months
Univariate Model / 8.43 (4.41) / 0.064 / 0.07
Multivariable Model 1* / 10.83 (4.64) / 0.026 / 0.09
Multivariable Model 2*** / 10.66 (1.70) / 0.012 / 0.27

Supplementary Table 4: Univariate Associations between Changes in Biochemical Markers of Inflammation and Atherosclerosis Progression on MRI

Biomarker / Percent Change in Mean Wall Thickness / Percent Change in Mean Wall Area
Beta Estimate (SE) / p-value / Beta Estimate (SE) / p-value
C-reactive protein / -1.112 (1.703) / 0.52 / -1.060 (2.214) / 0.63
Interleukin 6 / 1.189 (0.888) / 0.19 / 1.289 (1.159) / 0.27
MMP3 / 0.296 (0.327) / 0.37 / 0.292 (0.425) / 0.50
MMP-9 / 0.007(0.014) / 0.63 / 0.00746 (0.0184) / 0.69
MPO / 0.002 (0.011) / 0.85 / -0.002 (0.014) / 0.87
PAI-1 activity / -0.676 (0.595) / 0.26 / -0.952 (0.770) / 0.22
PLA2 / 0.0171 (0.097) / 0.86 / 0.030 (0.127) / 0.81
sE-selectin / -0.681 (0.414) / 0.11 / -0.796 (0.541) / 0.15
sP-selectin / 0.116 (0.285) / 0.69 / -0.004 (0.370027) / 1.00
sVCAM / -0.067 (0.029) / 0.027 / -0.079 (0.038) / 0.05
sICAM / -0.212 (0.107) / 0.0547 / -0.251 (0.140) / 0.08
TPA / 0.023 (0.341) / 0.95 / 0.035 (0.442) / 0.94

MMP = matrix metalloproteinase, MPO = Myeloperoxidase, PAI-1 = Plasminogen activator inhibitor-1, sICAM = Soluble intercellular adhesion molecule, sVCAM = Soluble vascular cell adhesion molecule

Supplementary Table 5: Association between percent changes in MWA and MWT at 24 months in participants with or without structural evidence of atherosclerosis progression on MRI at 6 months

Estimate (SE) / p-value / Adjusted R2 of Model
Association between increased MWT at 6 months and percent change in MWT at 24 months
Univariate Model / 27.65 (7.31) / <0.001 / 0.27
Multivariable Model 1* / 29.02 (7.82) / <0.001 / 0.27
Multivariable Model 2** / 15.97 (6.97) / 0.029 / 0.47
Association between increased MWA at 6 months and percent change in MWA at 24 months
Univariate Model / 45.33 (7.38) / <0.001 / 0.50
Multivariable Model 1* / 46.69 (7.91) / <0.001 / 0.49
Multivariable Model 2*** / 34.62 (8.04) / <0.001 / 0.56

3 Supplementary Figures:

Supplementary Figure 1: Summary of Participants Enrolled in Overall dal-PLAQUE Trial and Current Sub-study